WO1997003038A1 - Esters d'acides gras iodes, acides gras iodes et leurs derives, obtenus par iodohydrination, faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques - Google Patents

Esters d'acides gras iodes, acides gras iodes et leurs derives, obtenus par iodohydrination, faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques Download PDF

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Publication number
WO1997003038A1
WO1997003038A1 PCT/FR1996/001075 FR9601075W WO9703038A1 WO 1997003038 A1 WO1997003038 A1 WO 1997003038A1 FR 9601075 W FR9601075 W FR 9601075W WO 9703038 A1 WO9703038 A1 WO 9703038A1
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WO
WIPO (PCT)
Prior art keywords
oil
fatty acids
esters
iodized
derivatives
Prior art date
Application number
PCT/FR1996/001075
Other languages
English (en)
French (fr)
Inventor
Louis Jung
Yves Ingenbleek
Original Assignee
Louis Jung
Yves Ingenbleek
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE69629928T priority Critical patent/DE69629928T2/de
Priority to EA199800120A priority patent/EA001719B1/ru
Priority to AT96924964T priority patent/ATE249414T1/de
Priority to EP96924964A priority patent/EP0840720B1/fr
Priority to PL96324383A priority patent/PL185807B1/pl
Priority to US08/981,931 priority patent/US6124357A/en
Priority to AU65234/96A priority patent/AU6523496A/en
Priority to RO98-00028A priority patent/RO120337B1/ro
Priority to APAP/P/1998/001180A priority patent/AP874A/en
Priority to BR9609610-1A priority patent/BR9609610A/pt
Application filed by Louis Jung, Yves Ingenbleek filed Critical Louis Jung
Priority to UA98020668A priority patent/UA56142C2/uk
Publication of WO1997003038A1 publication Critical patent/WO1997003038A1/fr
Priority to BG102234A priority patent/BG63802B1/bg

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • the subject of the invention is esters of iodized fatty acids and iodized fatty acids and their derivatives, obtained by iodohydrination using aikylsilylated derivatives with alkaline iodides used in the treatment of endemic goiter and the pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and as a vehicle for chemoembolization.
  • Endemic goiter is a deficiency disease which is one of the most serious public health problems facing the World Health Organization (WHO).
  • Adolescent girls and women of reproductive age are the most exposed and can give birth to a high proportion reaching up to 10% of newborns suffering from a particular form of irreversible mental debility, called endemic cretinism, and considered as the the most daunting medical and social complication. It is universally recognized that the dietary iodine deficit is the primary and largely predominant cause of this nutritional scourge. The geological nature and the geographical environment thus appear as the main determinants of this situation, although certain nutritional factors are incriminated as aggravating secondary causes. The appropriate therapy will therefore consist in supplementing the deficient populations with iodized intakes covering physiological needs.
  • Lipiodol® iodized oil with a delay effect
  • This iodized oil designed as a product contrast in radiology, is made from rare and relatively expensive flaxseed oil (Somnifer papaverum).
  • a new iodized drug is proposed, formed from esters of iodized fatty acids or iodized fatty acids and their derivatives, of pharmaceutical purity, stable, devoid of toxic impurities, totally iodized, not having more double bonds, obtained by the action of an alkylsilylated reagent and an alkali metal iodide on fatty acid esters or fatty acids and having therapeutic properties.
  • methyl esters of iodized fatty acids obtained by an original synthesis from rapeseed oil (Brassica campestris) used as biological fuel for car engines with a very low cost price it is possible to manufacture low cost iodized fatty acid esters making it possible to envisage mass campaigns.
  • the new product ensures better bioavailability and a prolonged therapeutic effect because iodine is fixed on the three fatty acids (oleic acid n-9, linoleic acid n-6 and ⁇ -linolenic acid n-3) - the last two of which are essential - precursors of the three main metabolic pathways of lipids.
  • the administration of our iodized product is offered exclusively by oral route.
  • Hydroiodination with potassium iodide in orthophosphoric acid can also be considered (Organic. Synthesis, vol 9, 66).
  • Organic. Synthesis, vol 9, 66 As specified, inter alia, the German patent N ° C 07 C 69/62 / P 3513 323.8 of 13.4.1985 of W. KUHN et al.,
  • the methods of preparation of iodinated compounds lead to products containing toxic impurities, products that are not very stable in air and light during their preparation and storage.
  • Our preparation method leads in particular to a product with different constituents no longer exhibiting any double bond, a source of instability in particular in the presence of oxidation derivatives and free radicals.
  • Esters of fatty iodized acids prepared by iodohydrination involving aikylsilylated derivatives and an alkaline iodide, object of the invention are in the form of an oily, fluid, light yellow, stable, pharmaceutically pure liquid, with a relatively low cost price.
  • the fatty acid esters used for the preparation of iodinated derivatives involving an alkylsilylated compound and an alkali metal iodide can for example be triglycerides of fatty acids originating from vegetable oils, of the rapeseed oil, flaxseed oil, oil soy, safflower oil, peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil , palm oil and oils of animal origin.
  • the fatty acid esters used can also be mixtures of methyl esters or ethyl esters of fatty acids obtained from vegetable oils, such as rapeseed oil, flaxseed oil, soybean oil, safflower oil. , peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and oils of animal origin.
  • vegetable oils such as rapeseed oil, flaxseed oil, soybean oil, safflower oil.
  • Fatty acids such as oleic acid, linoleic acid, ⁇ -linolenic acid, erucic acid, arachidonic acid, ricinolic acid can also be used as raw materials.
  • the process for obtaining esters of iodized fatty acids or of iodized fatty acids consists in reacting an alkaline iodide with a halurealkylsilylated in organic medium giving rise in the presence of water to hydrodic acid in situ reacting either with the ester or esters of fatty acids, or with fatty acids.
  • esters of iodized fatty acids or of iodized fatty acids consists, for example, in reacting sodium iodide with chloride of trimethylsilyl or trimethylchlorosilane in acetonitrile followed by the action of water and the addition of either esters of unsaturated fatty acids or of unsaturated fatty acids.
  • iodohydrination of fatty acid esters can be carried out according to the following reaction:
  • the procedure for example for unsaturated fatty acid esters, is as follows: to a solution of 107.1 g of sodium iodide in 550 ml of acetonitrile is added under a nitrogen atmosphere and at 0 ° C., 89.25 ml of trimethylchlorosilane (or trimethylsilyl chloride). After the total addition of the trimethylchlorosilane, 6.65 ml of water is added dropwise. Then a solution of 70 g of unsaturated methyl or ethyl esters of rapeseed oil fatty acids is added. After 24 hours of reaction with stirring, the reaction is then stopped with 700 ml of water. The extraction is carried out with ether.
  • the organic phase is washed several times with a 10 percent sodium thiosulfate solution and then several times with water. It is dried over anhydrous sodium sulphate and the ether is evaporated at a temperature of 90 ° C. under 16 mm of Hg in order to remove the remains of silica ether. The residue is brown.
  • the esters of iodized fatty acids, dissolved in ether, are then discolored on charcoal and then filtered through alumina in order to remove the peroxides.
  • the ether is evaporated off and the traces of solvent are removed using a vane pump.
  • the mixture of iodized fatty acid esters obtained is golden yellow and has good fluidity.
  • This mixture can be characterized by 1 H NMR and 13C NMR spectrometry.
  • This method of synthesis of iodized fatty acid esters has been carried out on larger quantities.
  • Other water-immiscible solvents can be used.
  • the insolubility of sodium chloride in acetonitrile allows the total displacement of the reaction towards the formation of trimethylsilyl iodide.
  • This reaction is exothermic and allows the generation of hydroiodic acid and trimethylsilyl hydroxyl.
  • the product secondary SiM ⁇ 3 ⁇ H is eliminated after the iodohydrination reaction by simple evaporation under reduced pressure and washing with water. The iodohydrination reaction is followed visually by discoloration of the solution.
  • a 1 H NMR spectrum of the esters of iodized fatty acids in rapeseed oil makes it possible, by comparison with the spectrum of esters of non-iodized fatty acids in rapeseed oil, to verify the disappearance of the ethylenic protons. In addition, this makes it possible to control the absence of traces of diethyl ether solvent and of silica ether. Furthermore, a 13c NMR spectrum makes it possible to verify the disappearance of the carbons carrying the unsaturations.
  • the stability study is carried out by 1 H NMR, by thin layer chromatography and by an assay of iodine fixed on the fatty acid esters or on the fatty acids.
  • 1 H NMR spectra were performed after 2 months, 3 months and 8 months of storage at temperature 20-22 ° C protected from light. They are all three identical to the spectrum obtained during manufacture.
  • Thin layer chromatography sica gel plate GF 254 - mobile phase: diethyl ether / hexane 1:20 - examination under ultraviolet light at 254 nm and after spraying with a solution of phosphomolybdic acid R at 10 percent m / V in alcohol and heating the plate at 120 ° C.
  • the esters of iodized fatty acids were analyzed: the 1 H NMR spectrum was found to be identical to that of a freshly synthesized oil and the thin layer chromatography gave spots identical to those of the esters of freshly synthesized iodized fatty acids, and did not reveal no degradation product.
  • Tolerance test in rats before administering the mixture of iodized fatty acid esters of rapeseed oil to goitreous subjects, a tolerance test on the mixture of iodized esters is carried out on adult male rats 'about 300 g. Each test group consists of 5 rats which each receive an oral administration of 0.5 ml of a mixture of iodized fatty acid esters of rapeseed oil.
  • the rats are kept under observation. After one week, the behavior and general condition of the rats in each test group are normal and identical to those in the control group.
  • iodized products prepared according to the method described above are used as medicaments in general, for example as anti-goiter in the pure state or in combination with suitable excipients in the form of drinkable or ingestible liquid, capsules or ampoules by example.
  • iodized products can also be used as drugs by general or topical route, for example as contrast agents or as anti-inflammatory drugs in rheumatoid therapeutics.
  • These products can be used as drugs by general route or by local vascular route in the treatment of certain cancers by chemoembolization consisting in administering an anticancer cancer emulsified in esters of iodized fatty acids which act as vectors for lipophilic tumor cells.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fats And Perfumes (AREA)
PCT/FR1996/001075 1995-07-11 1996-07-10 Esters d'acides gras iodes, acides gras iodes et leurs derives, obtenus par iodohydrination, faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques WO1997003038A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
APAP/P/1998/001180A AP874A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof.
AT96924964T ATE249414T1 (de) 1995-07-11 1996-07-10 Verfahren zur herstellung jodierter fettsäuren und ihrer derivate durch jodwasserstoffanlagerung unter anwendung von alkylsilylderivaten mit alkalijodiden und deren pharmakologischen aktivitäten
EP96924964A EP0840720B1 (fr) 1995-07-11 1996-07-10 Prodede pour obtenir acides gras iodes et leurs derives par iodohydrination, faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques
PL96324383A PL185807B1 (pl) 1995-07-11 1996-07-10 Sposób otrzymywania jodowanego kwasu tłuszczowegoSposób otrzymywania jodowanego kwasu tłuszczowegolub jodowanego estru kwasu tłuszczowego lub ich jolub jodowanego estru kwasu tłuszczowego lub ich jodowanych pochodnych oraz ich zastosowanie do wytwadowanych pochodnych oraz ich zastosowanie do wytwarzania leków i do wytwarzania produktu kontrastowerzania leków i do wytwarzania produktu kontrastowegogo
US08/981,931 US6124357A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters iodinated fatty acids and derivatives thereof produced by iodohydrination using alkylsilylated derivatives and alkaline iodides and the pharmacological activities thereof
DE69629928T DE69629928T2 (de) 1995-07-11 1996-07-10 Verfahren zur herstellung jodierter fettsäuren und ihrer derivate durch jodwasserstoffanlagerung unter anwendung von alkylsilylderivaten mit alkalijodiden und deren pharmakologischen aktivitäten
RO98-00028A RO120337B1 (ro) 1995-07-11 1996-07-10 Procedeu de preparare a unor acizi graşi iodaţi, esteri ai acizilor graşi iodaţi şi a derivaţilor lor iodaţi şi utilizări farmaceutice ale acestora
AU65234/96A AU6523496A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivtives thereof, produced by iodohydrination using alkylsilylaed derivatives and alkaline iodides, and pharmacological actvities thereof
BR9609610-1A BR9609610A (pt) 1995-07-11 1996-07-10 ésteres de ácidos graxos iodados, ácidos graxos iodados e seus derivados, obtidos por iodohidrinação, envolvendo a introdução de derivados alquilsililados com iodetos alcalinos e suas atividades farmacológicas
EA199800120A EA001719B1 (ru) 1995-07-11 1996-07-10 Эфиры иодированных жирных кислот, иодированные жирные кислоты и их производные, способ их получения и применение в фармакологии
UA98020668A UA56142C2 (uk) 1995-07-11 1996-10-07 Йодована жирна кислота або естер йодованої жирної кислоти, або їх йодовані похідні, спосіб їх одержання
BG102234A BG63802B1 (bg) 1995-07-11 1998-02-05 Метод за получаване на естери на йодирани мастни киселини, йодирани мастни киселини и техни производни

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR95/08582 1995-07-11
FR9508582A FR2736549B1 (fr) 1995-07-11 1995-07-11 Esters d'acides gras iodes, acides gras iodes et leurs derives, obtenus par iodohydrination faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques

Publications (1)

Publication Number Publication Date
WO1997003038A1 true WO1997003038A1 (fr) 1997-01-30

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PCT/FR1996/001075 WO1997003038A1 (fr) 1995-07-11 1996-07-10 Esters d'acides gras iodes, acides gras iodes et leurs derives, obtenus par iodohydrination, faisant intervenir des derives alkylsilyles avec des iodures alcalins et leurs activites pharmacologiques

Country Status (21)

Country Link
US (1) US6124357A (enrdf_load_stackoverflow)
EP (1) EP0840720B1 (enrdf_load_stackoverflow)
CN (1) CN1077880C (enrdf_load_stackoverflow)
AP (1) AP874A (enrdf_load_stackoverflow)
AT (1) ATE249414T1 (enrdf_load_stackoverflow)
AU (1) AU6523496A (enrdf_load_stackoverflow)
BG (1) BG63802B1 (enrdf_load_stackoverflow)
BR (1) BR9609610A (enrdf_load_stackoverflow)
DE (1) DE69629928T2 (enrdf_load_stackoverflow)
EA (1) EA001719B1 (enrdf_load_stackoverflow)
FR (1) FR2736549B1 (enrdf_load_stackoverflow)
GE (1) GEP20002238B (enrdf_load_stackoverflow)
HU (1) HUP9901340A3 (enrdf_load_stackoverflow)
IN (1) IN185195B (enrdf_load_stackoverflow)
MA (1) MA23935A1 (enrdf_load_stackoverflow)
OA (1) OA10650A (enrdf_load_stackoverflow)
PL (1) PL185807B1 (enrdf_load_stackoverflow)
RO (1) RO120337B1 (enrdf_load_stackoverflow)
TR (1) TR199800031T1 (enrdf_load_stackoverflow)
UA (1) UA56142C2 (enrdf_load_stackoverflow)
WO (1) WO1997003038A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172192A1 (fr) * 2011-06-14 2012-12-20 R.I.Ph Esters d'acides gras iodés contenant au minimum 50 pour cent d'esters d'acide monoiodostéarique ou dérivés sous forme de capsule molle ou de gélule, utiles lors d'un accident nucléaire

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US6426367B1 (en) * 1999-09-09 2002-07-30 Efa Sciences Llc Methods for selectively occluding blood supplies to neoplasias
FR2891461B1 (fr) * 2005-09-30 2010-09-03 Jacques Theron Preparation medicamenteuse visqueuse injectable comprenant de l'ethanol et un compose liposoluble opaque aux rayons x.
CN101245007B (zh) * 2008-03-13 2011-03-23 武汉工程大学 一种稳定的碘化植物油脂肪酸乙酯的制备方法
CN107287029B (zh) * 2016-05-30 2021-04-06 江苏恒瑞医药股份有限公司 一种碘化植物油脂肪酸乙酯的制备方法
CN109251142A (zh) * 2017-07-12 2019-01-22 财团法人食品工业发展研究所 碘化脂肪酸乙酯的制备方法
CN109251144B (zh) * 2017-07-12 2021-06-18 财团法人食品工业发展研究所 碘化脂肪酸乙酯的制备方法
AU2018314406B2 (en) * 2017-08-07 2024-08-15 Université De Genève Nanoemulsion of iodinated fatty acids for CT imaging
CN110387286A (zh) * 2018-04-18 2019-10-29 江苏恒瑞医药股份有限公司 一种碘化植物油脂肪酸乙酯的制备方法
CN109438240B (zh) * 2018-09-10 2022-05-03 季珉 一种稳定的碘化亚油酸酯的制备方法
CN114606055B (zh) * 2020-12-08 2024-02-13 成都西岭源药业有限公司 一种去除碘化植物油脂肪酸乙酯中结合不稳定的碘的方法
JP2024530159A (ja) * 2021-08-02 2024-08-16 マイクロベンション インコーポレイテッド 医療画像用ヨウ素化脂肪酸
PL245039B1 (pl) * 2022-02-15 2024-04-22 Centrum Badan I Rozwoju Tech Dla Przemyslu Spolka Akcyjna Świeca bioaktywna oraz sposób wytwarzania świecy bioaktywnej.
WO2025145066A1 (en) * 2023-12-28 2025-07-03 Navinta, Llc An improved process for preparation of ethiodized oil

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JPS53119817A (en) * 1977-03-26 1978-10-19 Sinloihi Co Ltd Glycerilltri*22iodoohexadecanoate* and process for preparing same
DE3513323A1 (de) * 1985-04-13 1986-10-23 Merck Patent Gmbh, 6100 Darmstadt Stabilisierte iodfette und verfahren zu deren herstellung

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS53119817A (en) * 1977-03-26 1978-10-19 Sinloihi Co Ltd Glycerilltri*22iodoohexadecanoate* and process for preparing same
DE3513323A1 (de) * 1985-04-13 1986-10-23 Merck Patent Gmbh, 6100 Darmstadt Stabilisierte iodfette und verfahren zu deren herstellung

Non-Patent Citations (1)

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DATABASE WPI Week 7847, Derwent World Patents Index; AN 78-84825A, XP002006541 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012172192A1 (fr) * 2011-06-14 2012-12-20 R.I.Ph Esters d'acides gras iodés contenant au minimum 50 pour cent d'esters d'acide monoiodostéarique ou dérivés sous forme de capsule molle ou de gélule, utiles lors d'un accident nucléaire
FR2976491A1 (fr) * 2011-06-14 2012-12-21 R I P H Esters d'acides gras iodes contenant au minimum 50 pour cent d'esters d'acide monoiodo stearique ou derives sous forme de capsule molle ou de gelule, utile lors d'un accident nucleaire.

Also Published As

Publication number Publication date
US6124357A (en) 2000-09-26
AU6523496A (en) 1997-02-10
EP0840720B1 (fr) 2003-09-10
DE69629928D1 (de) 2003-10-16
BR9609610A (pt) 2002-05-07
IN185195B (enrdf_load_stackoverflow) 2000-12-02
BG102234A (en) 1998-09-30
FR2736549A1 (fr) 1997-01-17
EA199800120A1 (ru) 1998-10-29
AP874A (en) 2000-09-13
CN1143067A (zh) 1997-02-19
MA23935A1 (fr) 1997-04-01
ATE249414T1 (de) 2003-09-15
EP0840720A1 (fr) 1998-05-13
PL185807B1 (pl) 2003-08-29
RO120337B1 (ro) 2005-12-30
UA56142C2 (uk) 2003-05-15
BG63802B1 (bg) 2003-01-31
HUP9901340A2 (hu) 1999-09-28
GEP20002238B (en) 2000-09-25
PL324383A1 (en) 1998-05-25
DE69629928T2 (de) 2004-07-22
OA10650A (fr) 2002-09-18
FR2736549B1 (fr) 1997-10-10
EA001719B1 (ru) 2001-08-27
MX9800322A (es) 1998-09-30
HUP9901340A3 (en) 1999-11-29
TR199800031T1 (xx) 1998-05-21
CN1077880C (zh) 2002-01-16

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